The hypothesis is that age‑dependent depletion of mitochondrial deoxyribonucleoside triphosphates (dNTPs) skews mtDNA replication toward error‑prone pathways, increasing heteroplasmy and triggering retrograde signaling that alters nuclear histone acetylation, thereby accelerating aging. This links two observations: (1) replication errors (G→A/C→T transitions) dominate somatic mtDNA mutations with age [https://doi.org/10.1371/journal.pgen.1003794] and (2) the nuclear genome regulates mtDNA copy number and heteroplasmy dynamics [https://www.nature.com/articles/s41586-023-06426-5]. We propose that rescuing mitochondrial dNTP pools via supplementation with balanced deoxyribonucleosides reduces replication error rates, lowers heteroplasmy burden, and restores normal retrograde signaling, which in turn preserves youthful nuclear epigenetics and extends healthspan.

Testable predictions: (i) In wild‑type mice, lifelong supplementation with a deoxyribonucleoside mix (dA, dT, dG, dC) will decrease the accumulation of G→A/C→T mtDNA mutations in colon and brain compared with controls, measurable by ultra‑deep sequencing [https://elifesciences.org/articles/83395]. (ii) Treated mice will show reduced levels of senescence‑associated secretory phenotype (SASP) factors in tissues where mtDNA dysfunction patches arise, because impaired OXPHOS and NAD+ depletion are mitigated [https://pmc.ncbi.nlm.nih.gov/articles/PMC9246372/]. (iii) Nuclear histone acetylation patterns (e.g., H3K9ac, H3K27ac) in liver and muscle will remain closer to youthful profiles in supplemented animals, assessed by ChIP‑seq. (iv) Functional readouts such as grip strength, glucose tolerance, and frailty index will be significantly improved in the treatment group at 24 months of age.

Falsification: If nucleoside supplementation fails to lower mtDNA heteroplasmy, does not attenuate SASP markers, and does not preserve nuclear acetylation or healthspan relative to controls, the hypothesis is refuted. Conversely, a positive outcome would support the notion that mitochondrial nucleotide homeostasis is a upstream regulator of both mtDNA integrity and nuclear epigenetic aging, suggesting a combinatorial intervention strategy that targets the mitochondrial nucleotide pool alongside existing longevity approaches.